Background: There are 4 subtypes of Classical Hodgkin lymphoma (CHL) based on histologic morphology: Nodular Sclerosis (NS), Mixed Cellularity, Lymphocyte Rich, and Lymphocyte Depleted. Recently, the importance of the tumor microenvironment in CHL has become apparent, particularly in regard to macrophages and T-cell subsets and their prognostic significance. However, the differences in microenvironment and variations in background T-cell Th1 versus Th2 lineage committment among CHL subtypes has not been well characterized. In addition, CHL is known to have a bimodal age-dependent incidence with the young-adult peak predominantly associated with the NS subtype. Epidemiologic studies have suggested that this subtype of CHL in young-adults may have a separate and distinct etiologic cause.Design: 92 newly diagnosed cases of CHL were identified at LAC+USC Medical Center from 1999-2010, 54 of which were subtyped as NS-CHL. Tissue microarrays were constructed and the cases were phenotyped in duplicate or triplicate (specimen dependent) with in-situ hybridization and immunohistochemical stains including EBER, CD68, CD163, FOX-P3, and TBET (a marker for Th1-cell commitment). Positively stained cells were manually enumerated using scanned, standardized, 20x digital image fields. The count values were summarized with medians. The association analysis was based on a logistic regression for NS vs. non-NS subtypes adjusting for all markers and EBV status.Results: There was a statistically significant association identified between TBET expression and the NS subtype (p=0.008). TBET expression was significantly lower in patients with the NS subtype (median=1517 cells/mm2) compared to those diagnosed with a non-NS subtype of CHL (median=2175 cells/mm2). Further stratification of the NS vs. non-NS groups by age showed a clear decrease of TBET expression in the ≤35yrs group (median=1234 cells/mm2 for NS vs. 2474 cells/mm2 for non-NS), while the difference was not as pronounced in the >35yrs group (median=1956 cells/mm2 for NS vs. 2008 cells/mm2 for non-NS). In comparison, there were no apparent associations between expressivity of macrophage markers (CD68, CD163), Treg-cell markers (FOX-P3), or EBV status (EBER) in the microenvironment among the CHL subtypes.Conclusions: TBET expression is decreased in NS-CHL, and the difference appears more striking in younger patients. This finding lends support to Th1/Th2 disregulation as a contributing factor for NS-CHL, and possibly young-adult NS-CHL in particular.Category: Hematopathology